The three R’s of lung health and disease: repair, remodeling, and regeneration

Abstract

All tissues and organs can be classified according to their ability to repair and regenerate during adult homeostasis and after injury. Some exhibit a high rate of constant cell turnover, while others, such as the lung, exhibit only low-level cell regeneration during normal adult homeostasis but have the ability to rapidly regenerate new cells after injury. Lung regeneration likely involves both activation of progenitor cells as well as cell replacement through proliferation of remaining undamaged cells. The pathways and factors that control this process and its role in disease are only now being explored. In this Review, we will discuss the connection between pathways required for lung development and how the lung responds to injury and disease, with a particular emphasis on recent studies describing the role for the epithelium in repair and regeneration.Conflict of interest: The authors have declared that no conflict of interest exists.Citation for this article:

Lung Pericytes and Resident Fibroblasts

“…81 The functions of these genes and the effects of their risk-associated polymorphisms have drawn attention to the endoplasmic reticulum stress response, resilience, survival, and replenishment of lung epithelial cells. 15,75 Moreover, these connections between epithelial cell death and lung fibrosis help justify the continued and widespread use of lung epithelial injury by bleomcyin to cause fibrosis, despite this model's acknowledged flaws. 82 A strengthening hypothesis to generally explain fibrotic lung diseases is that injury or infection overcomes an already stressed epithelium's capacity for recuperation and engages innate immune pathways that may circumstantially promote or protect from harm.…”

“…82 A strengthening hypothesis to generally explain fibrotic lung diseases is that injury or infection overcomes an already stressed epithelium's capacity for recuperation and engages innate immune pathways that may circumstantially promote or protect from harm. 13,15,53,64,75,78,81 Myofibroblasts are the key effector cell type in fibrotic disease because they are dominant builders and remodelers of extracellular matrix that also exert strong force on their surroundings. 9,10,12e14,27,30,38,53,64,78,83 Myofibroblasts may be distinguished by expressing a-SMA and similar proteins in common with muscle, forming stress fibers, and by contractility.…”

“…79 But, the pathogenesis of fibrotic and degenerative lung diseases may also be considered developmental programs that fail to stop within the limits of homeostasis. 53,64,75 The programing to regenerate lung tissue clearly can operate as demonstrated (eg, by the similar pathways and epithelial-fibroblast communication activated to septate the alveoli during development and reactivated to recreate alveoli after pneumectomy). 1,22,75 The scientific and therapeutic challenges are to stimulate or limit these processes for beneficial changes.…”

“…13,15,16,53,78 However, these factors are also part of beneficial and self-limited wound healing, and epithelial restoration after injury is widely proposed to be the key difference between maintaining or losing lung function. 13,75,78,82 PGE 2 is a notable exception because it seems deficient in disease. Airway epithelial cells are capable of high PGE 2 output; PGE 2 suppresses fibroblast migration, proliferation, and myofibroblast differentiation; and PGE 2 levels are lower in IPF patients.…”

Clinical and Biological Implications of the Tumor Microenvironment

“…The coordinating interactions in forming, maintaining and repairing such an organ are therefore numerous and complicated. Subsequent research has shown that these interactions are mediated by contextdependant signaling mechanisms that are spatially and temporally precise and specific [17]. Expression of a particular mediator in a slightly inaccurate location or time can result in biochemical or structural defects and this applies to many different organ systems [18].…”